C9-ALS/FTD

IMED 7170

Andy Van Domelen

Overview

ALS-FTD

C9orf72

Healthy function

Hexanucleotide Repeat Expansion (HRE)

Pathogenic Mechanisms

Treatments

In the Clinic

Future Directions

ALS and FTD

Amyotrophic Lateral Sclerosis

Complex disease of motor neurons

Muscle and cognitive impairment

Familial and sporadic

Numerous molecular factors influence expression

ALS and FTD

Frontotemporal Dementia

Second most common form of pre-senile dementia

Frontal lobe degeneration and behavioral abnormalities

Familial and sporadic

Numerous molecular factors influence expression

QBI

ALS and FTD

ALS/FTD

Considerable clinical overlap

Shared Molecular Signatures / biomarkers

“Spectrum”

ALS and FTD

Why C9orf72?

  • Healthy C9orf72
  • HRE mutation
  • Pathology

C9orf72

Healthy C9orf72

Gene Structure

Isoforms

Normal Gene Function

Distribution in the body

C9orf72

Hexanucleotide Repeat Expansion (HRE)

Structure

Variable Repeat Numbers

Incomplete Penetrance

Variable Expressivity

Somatic Instability

Repeat Contraction

C9orf72 Pathogenic Mechanisms

Ranganathan 2020

C9orf72 Pathogenic Mechanisms

Haploinsufficiency

Hypermethylation

Dysregulated C9orf72 function

Immune phenotypes

Additive Effects

C9orf72 Pathogenic Mechanisms

RNA Foci

G-quadruplex structure

Sequester RNA-binding proteins

Frontal Cortex (FTD) and Spinal Cord (ALS)

Nucleolar stress

C9orf72 Pathogenic Mechanisms

Dipeptide Repeat (DPR) Proteins

Repeat-associated non-ATG (RAN) translation

Different DPRs = Different mechanisms

Selective Neuronal Vulnerability

C9orf72 Pathogenic Mechanisms

Other Molecules

TDP-43

p62

TBK1

C9-ALS/FTD

In the clinic

Diagnosis

Prognosis

Issues

  • Muscle Biopsy
  • Cognitive Tests
  • MRI
  • Fluid Tests
  • Family History
  • ALS: 20-48 months
  • FTD: 3-14 years
  • ALS/FTD: ~2.5 years
  • Disease mimics
  • Prolonged diagnosis time
  • False positives & false negatives

Key Takeaways